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Single-cell lineage tracing unveils a role for TCF15 in haematopoiesis
Nature ( IF 64.8 ) Pub Date : 2020-07-01 , DOI: 10.1038/s41586-020-2503-6
Alejo E Rodriguez-Fraticelli 1, 2, 3, 4 , Caleb Weinreb 5 , Shou-Wen Wang 5 , Rosa P Migueles 6 , Maja Jankovic 1, 2 , Marc Usart 1, 2 , Allon M Klein 5 , Sally Lowell 6 , Fernando D Camargo 1, 2, 3, 4
Affiliation  

Bone marrow transplantation therapy relies on the life-long regenerative capacity of haematopoietic stem cells (HSCs) 1 , 2 . HSCs present a complex variety of regenerative behaviours at the clonal level, but the mechanisms underlying this diversity are still undetermined 3 – 11 . Recent advances in single-cell RNA sequencing have revealed transcriptional differences among HSCs, providing a possible explanation for their functional heterogeneity 12 – 17 . However, the destructive nature of sequencing assays prevents simultaneous observation of stem cell state and function. To solve this challenge, we implemented expressible lentiviral barcoding, which enabled simultaneous analysis of lineages and transcriptomes from single adult HSCs and their clonal trajectories during long-term bone marrow reconstitution. Analysis of differential gene expression between clones with distinct behaviour revealed an intrinsic molecular signature that characterizes functional long-term repopulating HSCs. Probing this signature through in vivo CRISPR screening, we found the transcription factor TCF15 to be required and sufficient to drive HSC quiescence and long-term self-renewal. In situ, Tcf15 expression labels the most primitive subset of true multipotent HSCs. In conclusion, our work elucidates clone-intrinsic molecular programmes associated with functional stem cell heterogeneity and identifies a mechanism for the maintenance of the self-renewing HSC state. Using single-cell lineage tracing, the authors identify TCF15 as a novel regulator of haematopoietic stem cell quiescence and self-renewal.

中文翻译:

单细胞谱系追踪揭示了 TCF15 在造血中的作用

骨髓移植治疗依赖于造血干细胞 (HSC) 1、2 的终生再生能力。HSC 在克隆水平上呈现出多种复杂的再生行为,但这种多样性背后的机制仍未确定 3 – 11。单细胞 RNA 测序的最新进展揭示了 HSC 之间的转录差异,为它们的功能异质性提供了可能的解释 12-17。然而,测序分析的破坏性阻止了同时观察干细胞状态和功能。为了解决这一挑战,我们实施了可表达的慢病毒条形码,这使得在长期骨髓重建过程中能够同时分析来自单个成人 HSC 的谱系和转录组及其克隆轨迹。对具有不同行为的克隆之间差异基因表达的分析揭示了一种内在的分子特征,该特征表征了功能性长期重新增殖的 HSC。通过体内 CRISPR 筛选探索这一特征,我们发现转录因子 TCF15 是驱动 HSC 静止和长期自我更新所必需且足以驱动的。在原位,Tcf15 表达标记了真正多能 HSC 的最原始子集。总之,我们的工作阐明了与功能性干细胞异质性相关的克隆内在分子程序,并确定了维持自我更新 HSC 状态的机制。使用单细胞谱系追踪,作者将 TCF15 鉴定为造血干细胞静止和自我更新的新型调节剂。
更新日期:2020-07-01
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